{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T01:45:32Z","timestamp":1791596732659,"version":"4.3.4"},"reference-count":36,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T00:00:00Z","timestamp":1756771200000},"content-version":"vor","delay-in-days":1,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100008373","name":"Takeda Pharmaceutical Company","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008373","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp;amp; Dementia"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>INTRODUCTION<\/jats:title>\n                    <jats:p>\n                      Mutations in the\n                      <jats:italic>MAPT<\/jats:italic>\n                      gene that are causal for frontotemporal dementia (FTD) lead to mislocalization of tau protein to the neuronal cell body, changing microtubule dynamics to disrupt the nuclear envelope and nucleocytoplasmic transport.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      We report a high content imaging\u2010based phenotypic screen to identify novel small molecules that correct nuclear envelope defects in human neurons expressing the\n                      <jats:italic>MAPT<\/jats:italic>\n                      IVS10+16 mutation causal for FTD.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Screening a 19,786\u2010compound chemical diversity library, we identified &gt; 100 compounds that corrected nuclear membrane defects in\n                      <jats:italic>MAPT<\/jats:italic>\n                      IVS10+16 neurons, with 23 demonstrating robust dose\u2010dependent rescue. A common feature of hit compounds was alteration of the neuronal microtubule cytoskeleton, with a subset changing neuronal tau protein levels or phosphorylation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>Human models of tauopathy were used in a phenotypic screen to identify novel chemotypes that correct a validated pathology, illustrating the value of human models of neurodegenerative disease in the drug discovery process.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>A phenotypic screen for novel small molecules that suppress tau\u2010mediated pathologies was carried out in human frontotemporal dementia neurons.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>The key readout was correction of nuclear membrane defects, which are a pathological feature in tauopathies in vivo.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>The screen of 20,000 small molecules identified more than 20 compounds that corrected the phenotype in a dose\u2010dependent manner.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Hit compounds commonly altered microtubules, with a subset changing tau protein levels or phosphorylation.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.70620","type":"journal-article","created":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T09:16:23Z","timestamp":1756804583000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A phenotypic screen for novel small molecules that correct tau\u2010mediated pathologies in human frontotemporal dementia neurons"],"prefix":"10.1002","volume":"21","author":[{"given":"Hannah","family":"Maxwell","sequence":"first","affiliation":[{"name":"Talisman Therapeutics Babraham Research Campus  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Smith","sequence":"additional","affiliation":[{"name":"Talisman Therapeutics Babraham Research Campus  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Campbell","sequence":"additional","affiliation":[{"name":"Talisman Therapeutics Babraham Research Campus  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Clark","sequence":"additional","affiliation":[{"name":"Talisman Therapeutics Babraham Research Campus  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosanna","family":"La Rocca","sequence":"additional","affiliation":[{"name":"Talisman Therapeutics Babraham Research Campus  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Paonessa","sequence":"additional","affiliation":[{"name":"Talisman Therapeutics Babraham Research Campus  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergey","family":"Sitnikov","sequence":"additional","affiliation":[{"name":"Talisman Therapeutics Babraham Research Campus  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Evans","sequence":"additional","affiliation":[{"name":"Talisman Therapeutics Babraham Research Campus  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Maycox","sequence":"additional","affiliation":[{"name":"Neuroscience Drug Discovery Unit Takeda International  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6128-3372","authenticated-orcid":false,"given":"Frederick J.","family":"Livesey","sequence":"additional","affiliation":[{"name":"Talisman Therapeutics Babraham Research Campus  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,9,2]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/cm.21812"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/nan.12213"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010pathmechdis\u2010051222\u2010120750"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1080\/17460441.2023.2200245"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13784"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2018.07.039"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3639"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.12.085"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12847"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.14245"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593\u2010018\u20100194\u20101"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2023.07.006"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1252651"},{"key":"e_1_2_7_15_1","doi-asserted-by":"crossref","unstructured":"PaonessaF BizziniBD CampbellT et\u00a0al.Targeting the acetyltransferase NAT10 corrects pathologies in human frontotemporal dementia neurons and extends lifespan in an in vivo Drosophila tauopathy model.bioRxiv 2024. doi:10.1101\/2024.10.19.619211","DOI":"10.1101\/2024.10.19.619211"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.054521"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200509124"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2012.10.014"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.3389\/fragi.2023.1058968"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12015\u2010015\u20109599\u20103"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv246"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2012.116"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3041"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.107732"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3565(25)31589-2"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0006\u20108993(98)00407\u20107"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2015.11.039"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.03.015"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adk5693"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s44318\u201002500514\u20100"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsptsci.0c00077"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1177\/1087057115588287"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1177\/2472555218764678"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2017.02.006"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1101\/2023.10.09.561525"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.110913"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2013.04.003"}],"container-title":["Alzheimer's &amp; Dementia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/alz.70620","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/alz.70620","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/alz.70620","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,15]],"date-time":"2026-02-15T11:10:25Z","timestamp":1771153825000},"score":1,"resource":{"primary":{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/10.1002\/alz.70620"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9]]},"references-count":36,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2025,9]]}},"alternative-id":["10.1002\/alz.70620"],"URL":"https:\/\/doi.org\/10.1002\/alz.70620","archive":["Portico"],"relation":{},"ISSN":["1552-5260","1552-5279"],"issn-type":[{"value":"1552-5260","type":"print"},{"value":"1552-5279","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9]]},"assertion":[{"value":"2025-03-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-02","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70620"}}